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In a strange turn of events, the Indian Council of Medical Research (ICMR) issued a new advisory late on May 22 renewing its commitment to the use of hydroxychloroquine (HCQ) as a prophylactic against COVID-19 among India’s frontline healthcare workers.

While the previous advisory limited the drug’s use among workers treating COVID-19 patients, the new one reaches out to include “asymptomatic healthcare workers working in non-COVID hospitals/non-COVID areas of COVID hospitals/blocks” and “asymptomatic frontline workers, such as surveillance workers deployed in containment zones and paramilitary/police personnel involved in COVID-19 related activities”.

This is strange because the new advisory, while tacitly acknowledging that the previous one did not present clinical evidence in favour of the apex research body’s decision, presents subpar or insufficient evidence this time round to expand the scope of HCQ’s use instead of shrinking it – a paradoxical change.

By way of introduction and accountability, the advisory begins noting that “the Joint Monitoring Group under the Chairmanship of DGHS and including representatives from AIIMS, ICMR, NCDC, NDMA, WHO and experts drawn from Central Government hospitals reviewed the prophylactic use of HCQ in the context of expanding it to healthcare and other front line workers deployed in non-COVID and COVID areas, respectively.”

Further, the advisory states, “The National Task force for COVID-19 constituted by ICMR also reviewed the use of HCQ for prophylaxis of SARS-CoV-2 infection for high-risk population based on the emerging evidence on its safety and efficacy. The NTF reviewed the data on in-vitro testing of HCQ for antiviral efficacy against SARS-CoV-2, safety profile of HCQ reported to the pharmacovigilance program of India, and data on the use of HCQ for the prophylaxis of SARS-CoV-2 infection among healthcare workers and reported its findings”.

The task force’s data about the harmful side effects of HCQ use among India’s doctors and nurses is followed by the advisory mandating they undergo an electrocardiogram (ECG) test before taking the drug. This is also baffling because the emergence of side-effects, which many experts anticipated in investigative reports published by The Wire Science but which ICMR didn’t clarify before, should have given pause instead of encouragement.

According to the advisory, the side-effects among 1,323 healthcare workers were:

“… nausea (8.9%), abdominal pain (7.3%), vomiting (1.5%), hypoglycaemia (1.7%) and cardio-vascular effects (1.9%). However, as per the data from the pharmacovigilance programme of India, there have been 214 reported instances of adverse drug reactions associated with prophylactic HCQ use. Of these, 7 were serious individual case safety reports, with prolongation of QT interval on ECG in 3 cases.”

‘Absence of benefit’

The overarching fact is that HCQ has not been tested in clinical trials (although many are underway), whether in India or around the world, for its efficacy and safety as a prophylactic against COVID-19. Indeed, it has mostly been tested as treatment – i.e. for its ability to beat back the novel coronavirus in already symptomatic patients instead of for its ability to stave off an infection.

ICMR has in effect been interpreting the results of tests of ‘HCQ as treatment’ as results for prophylactic use as well – a line of reasoning that is not supported in science. There is also reason to believe the body could be cherry-picking the studies it chooses to interpret this way because many published studies note that HCQ may not be good treatment at all against COVID-19.

In fact, ICMR published its new advisory the same day results from an observational study involving over 15,000 patients and 81,000 controls were published in The Lancet. The journal noted “an absence of benefit of 4-aminoquinoline-based treatments in this population and suggest that they could even be harmful.” The chemical derivatives of 4-aminoquinoline include chloroquine and hydroxychloroquine. ‘This population’ refers to those who had tested positive for COVID-19 and were “hospitalised between December 20, 2019, and April 14, 2020”; they had a mean age of 53.8 years and 46.3% of them were women.

However, this study’s results have also been called into question, although this doesn’t directly change the fact that both of ICMR’s advisories on hydroxychloroquine are problematic. In fact, notwithstanding this critique, it’s unlikely that The Lancet study will sway ICMR’s mind about HCQ use. ICMR has cited three other observational studies in the new advisory to support its own position. All three studies appear to be much smaller than the one published in The Lancet. More importantly, they don’t present any published results nor do all their details appear in the Clinical Trial Registry of India. They are (quoting verbatim):

A retrospective case-control analysis at ICMR has found that there is a significant dose-response relationship between the number of prophylactic doses taken and frequency of occurrence of SARSCoV-2 infection in symptomatic healthcare workers who were tested for SARS-CoV-2 infection.

Another investigation from 3 central government hospitals in New Delhi indicates that amongst healthcare workers involved in COVID-19 care, those on HCQ prophylaxis were less likely to develop SARS-CoV-2 infection, compared to those who were not on it. The benefit was less pronounced in healthcare workers caring for a general patient population.

An observational prospective study of 334 healthcare workers at AIIMS, out of which 248 took HCQ prophylaxis (median 6 weeks of follow up) in New Delhi also showed that those taking HCQ prophylaxis had lower incidence of SARS-CoV-2 infection than those not taking it.

Note that the first study is retrospective and the third is prospective.

Observational studies are not clinical trials. The difference is that in observational studies, researchers can’t control who does or doesn’t receive the drug, and the drug’s effects are simply observed. On the other hand, in clinical trials, researchers can control which group of people receives the drug and which doesn’t – or at least set up two such groups of people after carefully selecting them for participation based on some preconditions. As such, they can fine-tune the study to answer specific questions about the drug’s safety and efficacy with greater precision.

In its previous advisory, ICMR had advised that India’s doctors and nurses who treat COVID-19 patients take two doses of HCQ on the first day – called a loading dose – of 400 mg each, followed by 400 mg per week. In the new advisory, ICMR recommends the following:

Healthcare workers who are “asymptomatic household contacts of laboratory confirmed cases” are advised to take “400 mg twice a day on day 1″ – the same loading dose as before – followed by 400 mg once weekly for the next three weeks, to be taken with meals”.

Other healthcare workers – i.e. “all asymptomatic healthcare workers involved in containment and treatment of COVID-19, and asymptomatic healthcare workers working in non-COVID hospitals/non-COVID areas of COVID hospitals/blocks” and “asymptomatic frontline workers, such as surveillance workers deployed in containment zones and paramilitary/police personnel involved in COVID-19 related activities” – are advised the same loading dose “followed by 400 mg once weekly for the next seven weeks, to be taken with meals”.

Further, the advisory concedes that “in clinical practice, HCQ is commonly prescribed in a daily dose of 200-400 mg for treatment of diseases such as rheumatoid arthritis and systemic lupus erythematosus for prolonged treatment periods with good tolerance.” But as health journalist Priyanka Pulla has reported for The Wire Science, this only means that the side-effects of HCQ are well-known among patients with lupus and rheumatoid arthritis, and doesn’t absolve the need to check for HCQ’s effects on people with neither disease and who are taking a higher dose.

The advisory further notes: “With available evidence for its safety and beneficial effect as a prophylactic drug against SARS-COV-2 during the earlier recommended 8 weeks period,” – what evidence is unknown – “the experts further recommend its use beyond eight weeks on weekly dosage with strict monitoring of clinical and ECG parameters, which would also ensure that the therapy is given under supervision.” Workers are to stop taking the drug if they notice “rare” side-effects, but the threshold of rarity has not been specified, only that they’re typically associated with cardiovascular issues.

The last major point of deviation from the previous advisory is that the new one mentions, albeit in a single line, that “the drug has to be given under strict medical supervision with informed consent.”

Informed consent is important for two reasons. As Pulla reported on May 7, it “is especially germane in the case of HCQ for COVID-19 [because] around the world, no drug regulator has approved HCQ as a prophylactic or as treatment for COVID-19 because there is little evidence that it works in this case.” The second reason is that ICMR’s own guidelines on the use of untested drugs during a crisis, such as a pandemic, require informed consent on the part of those taking the drug, and which was missing thus far.